Resveratrol has shown a strong chemopreventive effect against cancer. However, the molecular mechanisms by which resveratrol inhibits carcinogenesis are not clear. We will use COX-2 gene knockout mice and JB6, HaCaT and other cell culture systems to examine the anti-tumor promotion effect of resveratrol at the molecular level. Our hypothesis is that the inhibition of skin carcinogenesis by resveratrol occurs through an inhibition of COX-2 activity and induction of cell apoptosis. The specific aims to address the hypothesis are as follows: Specific Aim 1. To investigate whether the anti-skin carcinogenesis activity of resveratrol occurs through the COX-2 pathway by using the COX-2+/+ and COX-2-/ mouse model. Specific Aim 2. To investigate the role of COX-2 in resveratrol-induced cell death (apoptosis). Specific Aim 3. To determine the structure/activity relationship of resveratrol and its derivatives on cell transformation, apoptosis and phosphatidylinositol-3 (PI-3) kinases. We have established experimental conditions, including COX-2 knockout mice and cell lines, arid synthesis of resveratrol derivatives, in our preliminary studies. Our long-term goal is to identify the molecular mechanism explaining the anti-tumor effect exhibited by resveratrol. Such knowledge will help in developing better chemopreventive agents with fewer side effects.